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* From the Departments of Thoracic Surgery (Drs. Yasufuku, Nakajima, Sekine, Shibuya, and Fujisawa), Radiology (Dr. Motoori), and Basic Pathology (Dr. Hiroshima), Graduate School of Medicine, Chiba University, Chiba, Japan.
Correspondence to: Takehiko Fujisawa, MD, Professor and Chairman, Department of Thoracic Surgery, Graduate School of Medicine, Chiba University, 18-1 Inohana, Chuo-ku, Chiba 260-8670, Japan; e-mail: fujisawat{at}faculty.chiba-u.jp
Abstract
Study objectives: To perform a prospective comparison of direct real-time endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration (TBNA), positron emission tomography (PET), and thoracic CT for detection of mediastinal and hilar lymph node metastasis in patients with lung cancer considered for surgical resection.
Design: Prospective patient enrollment.
Setting: University teaching hospital.
Patients: One hundred two potentially operable patients with proven (n = 96) or radiologically suspected (n = 6) lung cancer were included in the study.
Interventions: CT, PET, and EBUS-TBNA were performed prior to surgery for the evaluation of mediastinal and hilar lymph node metastasis. The convex probe EBUS, which is integrated with a convex scanning probe on its tip, was used for EBUS-TBNA. Surgical histology was used as the "gold standard" to confirm lymph node metastasis unless patients were found inoperable for N3 or extensive N2 disease proven by EBUS-TBNA.
Main results: EBUS-TBNA was successfully performed in all 102 patients (mean age, 67.8 years) from 147 mediastinal and 53 hilar lymph nodes. EBUS-TBNA proved malignancy in 37 lymph node stations in 24 patients. CT identified 92 positive lymph nodes, and PET identified 89 positive lymph nodes (4 supraclavicular, 63 mediastinal, 22 hilar). The sensitivities of CT, PET, and EBUS-TBNA for the correct diagnosis of mediastinal and hilar lymph node staging were 76.9%, 80.0%, and 92.3%, respectively; specificities were 55.3%, 70.1%, and 100%, and diagnostic accuracies were 60.8%, 72.5%, and 98.0%. EBUS-TBNA was uneventful, and there were no complications.
Conclusion: Compared to CT and PET, EBUS-TBNA has a high sensitivity as well as specificity for mediastinal and hilar lymph node staging in patients with lung cancer. EBUS-TBNA should be considered for evaluation of the mediastinum early in the staging process of lung cancer.
Key Words: bronchoscopy endobronchial ultrasound lung cancer lymph node metastasis mediastinum positron emission tomography staging transbronchial needle aspiration
Lung cancer is the most common cause of cancer-related death in the Western world. The outcomes of the disease vary depending on early detection, histologic types of malignancy, and staging.1 Screening tests for early detection of lung cancer including low-dose spiral CT,2 sputum cytology screening,3 and autofluorescent bronchoscopy4 may increase the number of patients eligible for surgical resection. Histologic type of lung cancer can be diagnosed in 70 to 85% of patients by bronchoscopic and other noninvasive procedures.567 However, staging depends mainly on imaging procedures. Malignant involvement of the mediastinum is a highly significant prognosis factor for survival.8 Therefore, better preoperative staging will limit unnecessary surgical interventions, and patients will benefit more from surgical resection.9
Current American Thoracic Society guidelines for the staging of lung cancer suggest that contrast-enhanced CT should be considered the standard imaging technique for the evaluation of the mediastinum.10 Lymph nodes with the short-axis diameter > 1 cm on CT are suspected to be malignant. However, CT is neither sensitive nor specific for detecting metastasis in the mediastinum, since some benign nodes may be larger and small lymph nodes may be malignant.11 Hence, additional imaging such as positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) is required for a precise evaluation of the mediastinum. A metaanalysis12 comparing the test performance of FDG-PET and CT for mediastinal staging in patients with non-small cell lung cancer showed that FDG-PET is more accurate than CT for mediastinal staging. However due to the limited diagnostic specificity for identifying mediastinal metastases, tissue proof of PET-positive lesions are recommended to prove that the lesions are truly malignant before denying surgical resection.13
Tissue proof can be obtained by mediastinoscopy, the "gold standard" for mediastinal staging in lung cancer. However, it is invasive, requires general anesthesia, and often hospitalization.14 Therefore, different minimally invasive methods have been applied for tissue sampling. Conventional bronchoscopic transbronchial needle aspiration (TBNA) is a well-established technique, but the yield varies widely.151617 Efforts have been made to improve the yield by adding CT fluoroscopy guidance18 or the radial-type endobronchial ultrasound (EBUS) probe guidance.19 Furthermore, endoscopic ultrasound (EUS) with fine-needle aspiration (EUS-FNA) has been reported to have a high yield in the diagnosis of mediastinal lymph nodes.2021 However, all of these methods have limitations.
Another new minimally invasive method of mediastinal biopsy is direct real-time EBUS-guided TBNA using the convex probe (CP)-EBUS.2223 The aim of the present study was to compare the accuracy of the different staging tests (CT, PET, and EBUS-TBNA) for correct staging of the mediastinum in patients with lung cancer considered to be operable.
Materials and Methods
Patients
From December 2003 to March 2005, patients with suspected or pathologically established lung cancer referred to the Department of Thoracic Surgery, Chiba University Hospital were enrolled in this study. All patients were evaluated by history; physical examination; CBC count; renal, liver, and pulmonary function tests; chest radiography; CT scan of the chest and upper abdomen; brain MRI; bone scan; and FDG-PET. All tests were presented in a multidisciplinary session, and the staging of the disease, tumor resectability, and medical operability was verified by specialists. The primary tumor and lymph node status was classified according to the international TNM staging system reported by Mountain and Dressler.24
Patients were included in this prospective study if they were believed to be candidates for curative thoracic surgery from the multidisciplinary session. Following CT and PET, EBUS-TBNA was performed to evaluate mediastinal lymph nodes. The study was approved by the ethical committee of our institute, and written informed consent was obtained in all the patients included in the study.
Imaging Tests
Chest and upper abdominal CT were performed with contrast single injection and multidetector-row CT (Light Speed; GE Medical System; Milwaukee, WI). The slice thickness was 5 mm with a pitch of 1.6, and images were reconstructed at 5-mm intervals. It was used for the assessment of the resectability of the primary tumor, the evaluation of mediastinal lymph nodes, and the exclusion of distant metastases. Radiologists blinded to the results of other tests performed the scan reading and staged the patients accordingly by the criteria of Webb et al.25 Lymph nodes with the short axis > 1 cm were considered positive for malignancy.
Whole-body FDG-PET (GE PET Advance Nxi; GE Medical Systems) was performed followed by overnight fasting. The glucose levels of patients were within normal limits prior to examination. Sixty to 90 min after injection of 300 MBq of FDG, whole-body acquisition was performed. Images were reconstructed using the attenuation-weighted ordered-subset expectation maximization technique.26 Images were visually interpreted using a display of three orthogonal sections and maximum intensity projections. One experienced nuclear medicine physician (K.M., 12 years of experience) who was masked to the results of other tests read the PET images. Standardized uptake values were calculated as the ratio of the regional radioactivity concentration divided by the injected amount of radioactivity normalized to body weight.27 FDG-PET was considered positive for an N1, N2, or N3 lymph node if the PET report stated that there was hypermetabolic activity consistent with malignant disease (defined as standardized uptake value > 2.5).
EBUS-TBNA
EBUS-TBNA was performed with a flexible ultrasonic puncture bronchoscope with a linear scanning transducer with a frequency of 7.5 MHz on the tip (CP-EBUS; XBF-UC260F-OL8; Olympus; Tokyo, Japan) as previously described.2223 It scans parallel to the insertion direction of the bronchoscope and is connected to a dedicated ultrasound scanner (EU-C2000; Olympus) with Doppler-flow imaging for the detection of blood vessels. All procedures were performed by the same operator (K.Y.) under conscious sedation (midazolam).
Prior to EBUS-TBNA, a CT scan of the chest and a written report of the FDG-PET scan were available. The examination of all mediastinal lymph node stations accessible by CP-EBUS (stations 1, 2, 4, and 7) as well as the hilar lymph nodes (stations 10 and 11) was performed. After introduction, the bronchoscope was advanced into the main bronchus, and the hilar lymph nodes were observed. The subcarinal lymph nodes followed by lower paratracheal, upper paratracheal, and finally the highest mediastinal lymph nodes were visualized. For all lymph nodes visualized, frozen ultrasound images were obtained, and the sizes of the lymph nodes were measured in two dimensions by the placement of cursors. Lymph nodes with the short diameter > 5 mm were sampled with a dedicated 22-gauge TBNA needle (NA-201SX-4022; Olympus) under direct EBUS guidance. Different needles were used for each lymph node station; whenever N3 nodes were visualized, they were sampled first before N2 nodes. N1 nodes were punctured after N2 nodes. In addition, an internal sheath equipped with a needle that is withdrawn after passing the bronchial wall was used to avoid contamination during TBNA. The aspirated material was smeared onto glass slides. Smears were air dried as well as fixed in 95% alcohol. Dried smears were stained using Diff-Quik stain (American Scientific Products; McGaw Park, IL) and evaluated by an on-site cytopathologist to confirm adequate cell material. If adequate tissue was not identified by on site cytology after five passes, the procedure was terminated. Furthermore, Papanicolaou staining and light microscopy were performed by an independent cytopathologist who was blinded to the details of the cases. Specimens were categorized as positive (tumor cells), negative (lymphoid but no tumor cells), or inconclusive (poor cellularity).
A representative case of a patient who underwent FDG-PET, CT, and EBUS-TBNA prior to surgery is shown in Figure 1 and Figure 2 . Based on final surgical/pathologic diagnosis, CT and PET scan findings were false positive, while EBUS-TBNA result was true negative.
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Statistical Analysis
For CT, PET, and EBUS-TBNA, mediastinal lymph node staging was individually assessed either as N0, N1, N2, or N3. The results of each modality were compared to the final surgical/pathologic diagnosis confirmed by thoracotomy with complete mediastinal lymph node dissection. In case N3 or extensive N2 disease was confirmed by EBUS-TBNA and surgical resection not performed, the results were compared to clinical course consistent with malignant disease. The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy rate for prediction of lymph node staging was calculated using the standard definitions. The
2 test was used for comparison of the three modalities for the correct prediction of lymph node status.
Results
Patients
From December 2003 to March 2005, a total of 280 patients with suspected or pathologically established lung cancer were evaluated by the multidisciplinary group. Of these 280 patients, 178 patients were not further evaluated for presence of distant metastasis, tumor resectability, or medical operability. The remaining 102 patients with proven (n = 96) or suspected (n = 6) lung cancer fulfilled the criteria and underwent CT, PET, and EBUS-TBNA for mediastinal staging prior to surgery. The characteristics, final diagnosis, and the location of the target lesions in these 102 patients are shown in Table 1
. In the six suspected lung cancer cases with negative bronchoscopy findings prior to EBUS-TBNA, final diagnosis of lung cancer was obtained from tissue sampling of lymph nodes. In all, EBUS-TBNA was successfully performed in 147 mediastinal and 53 hilar lymph nodes. Thirty-seven lymph nodes were malignant and 163 were benign based on EBUS-TBNA (Table 2
). As a result, 24 patients were found to have N3 or extensive N2 disease. Of these 24 patients, 4 patients found to have minimal N2 disease had surgical resection of lung cancer with complete thoracic lymphadenectomy.
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EBUS-TBNA
EBUS-TBNA was performed in all 102 patients. The targeted lymph nodes are shown in Table 1. There were more right-sided paratracheal lymph nodes. In all, 147 mediastinal lymph nodes as well as 53 hilar lymph nodes were punctured. A firm diagnosis from cytology was obtained in all of the lymph nodes punctured. In 24 of 26 patients with mediastinal lymph node metastasis, EBUS-TBNA correctly diagnosed malignancy prior to surgery (92.3%) [Table 3]. The two patients with false-negative findings on EBUS-TBNA had N2 disease proven by complete lymphadenectomy. One of the two cases with false-negative findings is shown in Figure 3
. This patient had adenocarcinoma in the right lower lobe with metastasis in the subcarinal lymph node that was 15 x 8 mm in diameter on CT with calcification (Fig 3, top, A). This lymph node was negative for malignancy on PET as well. EBUS images also detected calcification within the node (Fig 3, center, B). EBUS-TBNA showed normal lymphocytes and therefore evaluated as N0 disease prior to surgery. However histology showed metastasis in half of the resected lymph node (Fig 3, bottom, C). In 76 patients, aspirates of mediastinal lymph nodes were negative for malignancy with normal lymphocytes without tumor cells, which were shown to be benign by surgery as well (Table 3). As a result, the sensitivity, specificity, positive predictive value, negative predicted value, and accuracy of EBUS-TBNA in the prediction of mediastinal lymph node staging were 92.3%, 100%, 100%, 97.4%, and 98.0%, respectively (Table 4).
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2 tests describing the correct prediction of the lymph node status, the outcome was highly significant (p < 0.00001). This means that there is a significant difference in the accuracy of the three different modalities. The mean examination time of EBUS-TBNA defined as the time from the first visualization of the nodes to the termination of the last puncture was 14.9 min (SD, 7.3 min; range, 4 to 29 min). The EBUS-TBNA procedure was uneventful, and there were no complications. All patients tolerated the procedure very well.
Discussion
Our report is the first study to compare CT, PET, and EBUS-TBNA for mediastinal staging of potentially operable lung cancer patients. EBUS-TBNA was performed in 102 potentially resectable patients with lung cancer or suspected lung cancer. The sensitivity, specificity, and accuracy of EBUS-TBNA for the prediction of mediastinal lymph node staging were 92.3%, 100%, and 98.0%, respectively. EBUS-TBNA was highly sensitive and specific compared to CT and PET. As a single procedure for mediastinal lymph node staging, EBUS-TBNA allows tissue diagnosis, which is extremely helpful and provides superior diagnostic accuracy compared to PET.
There are many studies282930 comparing CT and PET for mediastinal staging, and a metaanalysis12 comparing the two modalities has shown that PET is more accurate than CT. For CT, the median sensitivity and the specificity were 61% (interquartile range, 50 to 71%) and 79% (interquartile range, 66 to 89%), respectively. For FDG-PET, the median sensitivity and specificity were 85% (interquartile range, 67 to 91%) and 90% (interquartile range, 82 to 96%), respectively. In addition, FDG-PET was more sensitive but less specific when CT showed enlarged lymph nodes. The result of our study for the diagnostic accuracy of thoracic CT was consistent with results from previous reports. However, the specificity of PET was lower than previously reported.12 This may be due to the fact that the study group consisted of operable lung cancer patients who usually have only small lymph nodes on CT. In fact, the median size of the lymph nodes accessed were only 12.8 x 8.7 mm in diameter, and the short axis of 40 of 147 mediastinal lymph nodes was only 5 mm. It should be noted that in our study, EBUS-TBNA correctly diagnosed each of these small lymph nodes as malignant or benign.
Although PET is significantly superior to CT in detecting mediastinal involvement and may be useful to detect distant metastases, inflammatory reactions of lymph nodes may lead to accumulation of FDG, resulting in false-positive results. Therefore, false-positive PET findings in the mediastinum may be frequently seen, and many authors113132 have suggested that tissue confirmation is necessary before denial of surgery. In the present study, there were 23 false-positive findings that were all correctly diagnosed as false positive by EBUS-TBNA prior to surgery. EBUS-TBNA avoided more invasive procedures such as mediastinoscopy and video-assisted thoracic surgery. Our data support the suggestions from these authors.113132
FDG-PET provides biological information on tissues by evaluating glucose metabolism. Therefore, FDG uptake is not tumor specific and is often observed in inflammatory lesions and benign diseases.33 Attempts have been made to clarify the causes of false-positive PET results. Shiraki et al34 reported that false-positive results of FDG-PET in hilar and mediastinal lymph nodes were closely related to the size of lymph node and the volume of macrophages. Sixteen of 23 false-positive cases that we experienced were also evaluated as N2 disease by CT. The short axis of the PET hot spot lymph nodes in these patients was > 10 mm. These results suggest that enlarged mediastinal lymph nodes with FDG accumulation should be confirmed by biopsy. EBUS-TBNA allows safe and accurate cytologic evaluation that will easily differentiate the nature of the lymph nodes as shown in this study.
When performing biopsy from the airway, there always remain possibilities of a false-positive result. It is safe to say that cytology and/or histology positive for malignancy is a true positive. Therefore, a false positive is usually related to a contaminant in the TBNA process. In our study, there are several lines of evidence against a contamination during the process. First of all, there were no changes in the bronchial airway at the site of puncture. Since the lymph nodes are adjacent to the bronchial wall, there is a low possibility of contamination. Secondly, the dedicated 22-gauge needle is equipped with an internal sheath that is withdrawn after the puncture of the bronchus. This sheath allows for the prevention of contamination. Collectively, it suggests that there is a low chance of contaminations during the puncture process and that there were no false-positive cases in our study. However we should always be aware of the fact that there is a chance of a false-positive EBUS-TBNA result.
In our study, we did not evaluate other possible methods available for obtaining samples from the mediastinal lymph nodes such as TBNA, EUS-FNA, and mediastinoscopy. However, it is hard to compare these techniques because of the difference of potential to assess different portions of the mediastinum (Fig 4 ). Conventional TBNA can be performed during bronchoscopy, which is usually performed in lung cancer patients avoiding separate staging procedures.151617 This is a big advantage, as in EBUS-TBNA. Conventional TBNA has same access to lymph nodes as does EBUS-TBNA. However, it is a blind procedure preventing target visualization, and therefore the yield for TBNA varies widely.151617 From the results of the study by Herth et al,19 who compared EBUS-guided TBNA to TBNA, we speculate that EBUS-TBNA has a higher yield compared to conventional TBNA. EUS-FNA is an accurate technique for the analysis of mediastinal lymph nodes from the esophagus. Due to its high accuracy and safety, it is increasingly used for the staging of lung cancer.2021 Although EUS-FNA has excellent access to the posterior nodes (stations 5, 7, 8, and 9), it is unable to image the anterior mediastinum where most of the mediastinal lymph nodes made be involved as in our current study.
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From the results of our study, we may create an algorithm for the evaluation of the mediastinum. Patients with an abnormal shadow suspected of lung cancer should be initially evaluated by CT. If there are enlarged lymph nodes, PET may be performed. During the diagnostic bronchoscopy, EBUS-TBNA of enlarged lymph nodes or PET-positive lymph nodes should be performed if the lymph nodes of interest are within the reach of EBUS-TBNA, ie, in the highest mediastinal, paratracheal, subcarinal, or hilar lesions. If a result from cytology is negative for malignancy, mediastinoscopy should be considered for confirmation of the absence of mediastinal involvement. If there are enlarged and/or PET-positive lymph nodes in stations 5, 8, or 9, other invasive procedures such as EUS-FNA and thoracoscopy should be considered.
In conclusion, EBUS-TBNA has a high sensitivity as well as specificity compared to CT or PET for mediastinal staging in patients with potentially resectable lung cancer. Tissue confirmation obtained by EBUS-TBNA is especially important for accurate staging. It should be considered for evaluation of the mediastinum early in the staging process of lung cancer.
Footnotes
Abbreviations: CP = convex probe; EBUS = endobronchial ultrasonography; EUS = endoscopic ultrasound; FDG = 18F-fluorodeoxyglucose; FNA = fine-needle aspiration; PET = positron emission tomography; TBNA = transbronchial needle aspiration
All authors have no conflicts of interest to disclose.
Supported by a grant from The Japanese Foundation for Research and Promotion of Endoscopy to Dr. Yasufuku.
Received for publication November 14, 2005. Accepted for publication February 23, 2006.
References
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